Correlation of the total superoxide dismutase activity between joint fluid and synovium in end-stage knee osteoarthritis.

Recently, we found significantly reduced total superoxide dismutase (SOD) activity in the cartilage of patients with end-stage knee osteoarthritis (OA). In this study, we aimed to evaluate the SOD activity in serum, joint fluid, cartilage, and synovial membrane samples collected from 52 patients with end-stage knee OA who underwent total knee arthroplasty. The relationship between the total SOD activity in each tissue was evaluated using Spearman's rank correlation coefficient. The joint fluid total SOD activity was used as the objective variable, and its association with the serum, cartilage, and synovial total SOD activities was evaluated using multiple linear regression analysis. Univariate analysis revealed that joint fluid total SOD activity was positively correlated with synovial total SOD activity. Multiple linear regression analysis using joint fluid total SOD activity as the objective variable showed a positive association with synovial total SOD activity (ß = 0.493, adjusted R2 = 0.172, P < 0.01). In patients with end-stage knee OA, the state of the synovial total SOD activity is better reflected by the total SOD activity in the joint fluid than that in the cartilage. Joint fluid total SOD activity may serve as a biomarker for the treatment and prevention of synovitis.

Superoxide dismutase activity is significantly lower in end-stage osteoarthritic cartilage than non-osteoarthritic cartilage.

Recent studies have shown that superoxide dismutase 1 (SOD1), SOD2, and SOD3 are significantly decreased in human osteoarthritic cartilage. SOD activity is a marker that can be used to comprehensively evaluate the enzymatic capacities of SOD1, SOD2, and SOD3; however, the trend of SOD activity in end-stage osteoarthritic tissues remains unknown. In the present study, we found that SOD activity in end-stage osteoarthritic synovium of the knee was significantly lower than that in control synovium without the influence of age. The SOD activity was significantly lower in the end-stage knee osteoarthritic cartilage than in the control, but a weak negative correlation was observed between aging and SOD activity. However, SOD activity in end-stage hip osteoarthritic cartilage was significantly lower than that in control cartilage without the influence of aging. The relationship between osteoarthritis and SOD activity was stronger than the relationship between aging and SOD activity. These results indicate that direct regulation of SOD activity in joint tissues may lead to suppression of osteoarthritis progression.

Mid and long term outcomes after fixation of osteochondritis dissecans.

OBJECTIVE: To assess the longitudinal outcomes of osteochondritis dissecans (OCD) fixation and to detect the influencing factor for the results of OCD. METHODS: 22 OCD fixation using bioabsorbable pins were assessed Lysholm score, Tegner activity scale and KOOS4 at preoperative, postoperative short (3.0 years) and mid-long (11.9 years) term. RESULTS: Postoperative Lysholm score was significantly better than the preoperative time. There was no factor influencing KOOS4 at mid-long term. CONCLUSION: OCD fixation contributes good results for a long time regardless of skeletal maturity, the size and the severity of OCD.

Association of medial meniscal extrusion with medial tibial osteophyte distance detected by T2 mapping MRI in patients with early-stage knee osteoarthritis.

BACKGROUND: Medial meniscal extrusion (MME) is associated with progression of medial knee osteoarthritis (OA), but no or little information is available for relationships between MME and osteophytes, which are found in cartilage and bone parts. Because of the limitation in detectability of the cartilage part of osteophytes by radiography or conventional magnetic resonance imaging (MRI), the rate of development and size of osteophytes appear to have been underestimated. Because T2 mapping MRI may enable us to evaluate the cartilage part of osteophytes, we aimed to examine the association between MME and OA-related changes, including osteophytes, by using conventional and T2 mapping MRI. METHODS: Patients with early-stage knee OA (n = 50) were examined. MRI-detected OA-related changes, in addition to MME, were evaluated according to the Whole-Organ Magnetic Resonance Imaging Score. T2 values of the medial meniscus and osteophytes were measured on T2 mapping images. Osteophytes surgically removed from patients with end-stage knee OA were histologically analyzed and compared with findings derived by radiography and MRI. RESULTS: Medial side osteophytes were detected by T2 mapping MRI in 98% of patients with early-stage knee OA, although the detection rate was 48% by conventional MRI and 40% by radiography. Among the OA-related changes, medial tibial osteophyte distance was most closely associated with MME, as determined by multiple logistic regression analysis, in the patients with early-stage knee OA (ß = 0.711, p < 0.001). T2 values of the medial meniscus were directly correlated with MME in patients with early-stage knee OA, who showed ≥ 3 mm of MME (r = 0.58, p = 0.003). The accuracy of osteophyte evaluation by T2 mapping MRI was confirmed by histological analysis of the osteophytes removed from patients with end-stage knee OA. CONCLUSIONS: Our study demonstrates that medial tibial osteophyte evaluated by T2 mapping MRI is frequently observed in the patients with early-stage knee OA, showing close association with MME, and that MME is positively correlated with the meniscal degeneration.

Serum interleukin 6 levels are associated with depressive state of the patients with knee osteoarthritis irrespective of disease severity.

This cross-sectional study investigated the prevalence of depressive state and association between depressive state and serum interleukin (IL)-6 levels in knee osteoarthritis (OA) patients. A total of 115 painful knee OA patients were enrolled and divided into two groups according to the radiographic OA severity. Pain was evaluated using a visual analog scale (VAS). Depressive state was assessed by the self-rating depression scale (SDS). Serum IL-6 levels were also measured. Pearson's correlation coefficient was used to assess the correlation between the variants tested, and logistic regression analysis was used to identify factors associated with the depressive state. Fifty-two percent of the patients had an SDS score of ≥ 40, which is indicative of the depressive state. The pain VAS score (r = 0.22, p = 0.02) and serum IL-6 level (r = 0.31, p < 0.01) were independently associated with the SDS score of all early-stage knee OA patients (Kellgren-Lawrence [K/L] grade 2). However, only the serum IL-6 level was independently associated with the SDS scores of advanced-stage knee OA patients (K/L grades 3 and 4, r = 0.36, p < 0.01). A logistic regression analysis revealed that serum IL-6 level was the variable for the SDS score [odds ratio 1.41 (95% confidence interval 1.03-1.94, p < 0.03)]. Approximately half of the knee OA patients were found to be in the depressive state, and their serum IL-6 levels to be associated with the depressive state, irrespective of OA severity.

Preoperative timed single leg standing time is associated with the postoperative activity of daily living in aged disabled patients with end-stage knee osteoarthritis at six-months after undergoing total knee arthroplasty.

OBJECTIVES: The aim of the present study was to investigate the effect size (ES) of total knee arthroplasty (TKA) for the symptoms and lower limb function and identify preoperative factor(s) associated with the post-operative activity of daily living (ADL) in aged patients with end-stage knee OA undergoing TKA. METHODS: Fifty-nine aged patients with end-stage knee OA (mean age: 74.6 years) were enrolled in this study. The symptoms and lower limb function of the patients were evaluated using the Japanese Knee Osteoarthritis Measure (JKOM), the timed up and go (TUG) test and timed single-legged stance test with eyes open (TSLS) before and after six months from the operation. RESULTS: While the ES of TKA for the improvement of pain was 2.83, the ES of TKA for the improvement of ADL, TUG and TSLS were 1.30, 0.59, and 0.49, respectively. While the post-operative ADL score was not associated with the preoperative ADL or pain scores, it was associated with the preoperative TUG and TSLS scores. A multiple regression analysis revealed that the one preoperative factor associated with the postoperative ADL was the TSLS. CONCLUSION: The preoperative TSLS is associated with the postoperative ADL in aged disabled patients with end-stage knee OA.

A novel patient-reported outcome measure for anterior cruciate ligament injury: evaluating the reliability, validity, and responsiveness of Japanese anterior cruciate ligament questionnaire 25.

PURPOSE: Despite objectively good results, up to 70 % of individuals may not return to their pre-injury level of sports activity after anterior cruciate ligament (ACL) reconstruction surgery. Although psychological responses have been shown to affect outcomes after ACL injury, an appropriate means of measuring their effects, in addition to functional status, has not been determined. The purpose of this study was to develop a patient-reported questionnaire for measuring psychological factors associated with outcomes after ACL injury and to evaluate its reliability, validity, and responsiveness. METHODS: After item analysis based on the results of two pilot studies and a short relevance assessment, 25 questionnaire items were selected for the Japanese Anterior Cruciate Ligament Injury Questionnaire 25 (JACL-25) and assessed for validity, reliability, and responsiveness in subjects with ACL injury. RESULTS: The JACL-25 had no floor or ceiling effects and no confounding factors. A Cronbach's alpha coefficient of 0.981 and a Guttman split-half coefficient of 0.983 indicated excellent reliability. Large standardized response means (1.30-1.62) and effect sizes (0.96-1.51) from the preoperative to postoperative period indicated good responsiveness. Construct structures were created, and these items were separated into three domains. Strong correlations between the JACL-25 and the International Knee Documentation Committee Subjective Knee Form (r s = -0.86), Lysholm Score (r s = -0.73), and Tegner Activity Scale (r s = -0.65) indicated good concurrent validity of the JACL-25. CONCLUSIONS: The present study demonstrated that the JACL-25 was valid, reliable, and responsive enough to evaluate psychological factors associated with outcomes in individuals with ACL injuries. LEVEL OF EVIDENCE: Diagnostic study, Level III.

Preoperative assessments completed for anterior cruciate ligament reconstructions with remnant preservation.

The purpose of this study was to investigate the preoperative characteristics that are necessary to be able to perform reconstructions of the anterior cruciate ligament (ACL) with remnant preservation. The preoperative period was significantly shorter for patients in patients who received a reconstruction with remnant preservation than for those without remnant (3.9 months vs 16.0 months, p < 0.01). The cut-off time to be able to reconstruct an ACL with remnant preservation were 2.5 months. The preoperative period is important to perform an ACL reconstruction with remnant preservation.

Diagnoses of psychiatric disorders in hypothetical patients by non-psychiatric physicians in Japan.

OBJECTIVE: This study was undertaken to investigate non-psychiatric physicians' diagnoses of hypothetical patients in clinical scenarios with comorbid medical and psychiatric disease in Japan. METHODS: The non-psychiatric physicians were asked to diagnose eight clinical scenarios describing several typical behavioral health problems in the medical settings. RESULTS: A total of 155 non-psychiatric physicians participated. Many physicians had problems correctly diagnosing depression and hypoactive delirium with medically ill patients. CONCLUSIONS: It is time to incorporate new efficient and effective approaches, such as collaborative care system and proactive delirium prevention programs, to improve overall behavioral health diagnosis and treatment, rather than relying on the rapid recognition of behavioral health problems in primary care/general medical settings.

Intra-articular hyaluronic acid injection versus oral non-steroidal anti-inflammatory drug for the treatment of knee osteoarthritis: a multi-center, randomized, open-label, non-inferiority trial.

INTRODUCTION: While many of the commonly used conservative treatments for knee osteoarthritis (OA) have been recognized to be effective, there is still insufficient evidence available. Among the pharmacological treatments for knee OA, oral non-steroidal anti-inflammatory drugs (NSAIDs) act rapidly and are recommended for the management of OA. However, frequent and serious adverse effects of NSAIDs have been recognized. Intra-articular injections of hyaluronic acid (IA-HA) for the treatment of knee OA have been shown to reduce pain and improve joint function. However, there has been no qualified direct comparison study of the efficacy and safety between IA-HA and NSAIDs for patients with knee OA. The aim of this study was to clarify the efficacy and safety of early-phase IA-HA in comparison to those of NSAIDs for patients with knee OA. METHODS: This multicenter, randomized, open-label, parallel-group, non-inferiority comparison study with an oral NSAID involved a total of 200 patients with knee OA. An independent, computer-generated randomization sequence was used to randomly assign patients in a 1:1 ratio to NSAIDs three times per day for five weeks (n = 100) or IA-HA once a week for five weeks (n = 100). The primary endpoint was the percentage change in the patient-oriented outcome measure for knee OA, the Japanese Knee Osteoarthritis Measure (JKOM) score. All patients were questioned regarding any adverse events during treatment. The full analysis set (FAS) was used for analysis. The margin of non-inferiority was 10%. RESULTS: The analyses of primary endpoint included 98 patients in the IA-HA group and 86 patients in the NSAID group. The difference in the percentage changes of the JKOM score between the two intervention arms (IA-HA; -34.7% (P<0.001), NSAID; -32.2% (P<0.001)) was -2.5% (95% confidence interval (CI): -14.0 to 9.1), indicating IA-HA was not inferior to NSAID. The frequency of both withdrawal and adverse events in the IA-HA group were significantly lower than those in the NSAID group (P = 0.026 and 0.004, respectively). CONCLUSIONS: The early efficacy of IA-HA is suggested to be not inferior to that of NSAIDs, and that the safety of the early phase of IA-HA is superior to that of NSAIDs for patients with knee OA. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR), UMIN000001026.

Disability for daily living is a predictor for joint replacement in patients with end-stage knee osteoarthritis.

The objective indicators which reflect the past results of end-stage knee osteoarthritis (OA) patients who have already received total knee arthroplasty (TKA) could be helpful for physicians to discuss with patients who are considering TKA. The aim of this prospective cohort study was to examine whether we could predict the knee OA patients who would receive TKA in advance based on baseline data, and to set cut-off points for receiving TKA. The two-hundred and forty end-stage medial-type knee OA patients were enrolled and followed up for 6 months while performing therapeutic exercises. Radiographic findings, visual analog scale for pain and a patient-oriented outcome measure, the Japanese Knee Osteoarthritis Measure (JKOM), were recorded at baseline. Relative risks (RRs) using the area under the curve (AUC) for a receiver operating characteristic (ROC) curve were calculated to evaluate several scores for receiving TKA. While 119 patients (55.3 %) did not undergo TKA, the remaining 96 patients (44.7 %) underwent TKA during this period. The AUCs of the ROC curve for the JKOM total score [0.71 (95 % CI 0.64-0.79)] were higher than those for radiographic parameters. Among the JKOM subcategories, JKOM category III, which indicates the condition in daily life, showed the highest AUC of 0.72 (0.65-0.80). The JKOM total score (65/100) and JKOM category III score (17/40) showed RRs of 2.20 (1.33-3.63) and 1.95 (1.18-3.22) for receiving TKA, respectively. The presence of disability in daily living was found to be an important factor determining whether the patient should undergo TKA.

[A study on the antiemetic effect and extrapyramidal symptoms of prochlorperazine versus perospirone for the control of nausea and vomiting due to opioid introduction].

Prochlorperazine is often used to prevent opioid-induced nausea; however, this drug causes extrapyramidal symptoms. It is important to determine the incidence of such symptoms and identify coping mechanisms because these symptoms induce intense and possibly life-threatening patient suffering. The purpose of this study was to determine the incidences of nausea and extrapyramidal symptoms associated with the use of prochlorperazine and perospirone as preventive antiemetics when initiating opioid treatment(a sustained-release tablet of oxycodone at a dose of 10 mg/day)and to compare the benefits of the 2 drugs. A total of 100 cancer patients who received medical care from a physician in the palliative care department of our center between May 2007 and September 2008 were consecutively enrolled for a retrospective review of the medical records. Of the patients, 50 had received prochlorperazine treatment(10 or 15 mg/day, orally)and 50 had received perospirone treatment(4 or 8 mg/day, orally)concomitantly with oxycodone treatment(10 mg/day)on an in-patient or outpatient basis. The incidence of nausea and vomiting within 1 week after starting treatment with opioids and the extrapyramidal symptoms during treatment were evaluated. The results showed that the incidence of nausea and vomiting was 8. 0% for the prochlorperazine group and 4. 0% for the perospirone group, and this difference was not statistically significant; however, the incidence of extrapyramidal symptoms was significantly higher for the prochlorperazine group(14%)than for the perospirone group(0%). Furthermore, the extrapyramidal symptom observed in the prochlorperazine group was akathisia, which occurred within a week. The results of this study suggest that careful attention should be paid so as not to overlook akathisia when using prochlorperazine as an antiemetic in cancer patients and that atypical antipsychotics, such as perospirone, could be used as alternatives.

Synovial perlecan is required for osteophyte formation in knee osteoarthritis.

The osteophyte associated with osteoarthritis (OA) is a bony outgrowth formed at the margins of the affected joint through endochondral ossification-like processes. However, the mechanism of osteophyte formation and its pathogenesis are unclear. Perlecan (Hspg2), a heparan sulfate proteoglycan, is expressed in many extracellular tissues and plays critical roles in skeletal development and diseases. The aim of the present study is to identify the role of synovial perlecan in osteophyte formation using perinatal lethality rescued perlecan-knockout mice (Hspg2(-/-)-Tg) wherein perlecan expression is lacking in the synovial and other tissues, except for cartilage. We analyzed the development of osteophytes in joints of Hspg2(-/-)-Tg mice in two different animal models: the surgical OA model, in which the medial collateral ligament was transected and the medial meniscus was resected, and the TGF-ß-induced osteophyte formation model. In the surgical OA model, the osteophyte size and maturation were significantly reduced in the OA joints of Hspg2(-/-)-Tg mice compared with control mice, while OA developed on the medial side of the knee joints with no differences in the cartilage degradation score or synovitis score between control and Hspg2(-/-)-Tg mice. The reduced osteophyte formation in Hspg2(-/-)-Tg mice was associated with reduced cell proliferation and chondrogenesis. In the TGF-ß model, the osteophyte size and maturation were also significantly reduced in Hspg2(-/-)-Tg mice compared with control mice. Our findings suggest that synovial perlecan plays an important role in osteophyte development in OA, and they provide insights that may facilitate the development of OA therapy.

Reference intervals of serum hyaluronic acid corresponding to the radiographic severity of knee osteoarthritis in women.

BACKGROUND: While serum levels of hyarulonic acid (sHA) is known to be useful for a burden of disease biomarker in knee OA, it is far from practical. The reference intervals must be established for biomarkers to be useful for clinical interpretation. The aim of this study was to establish the reference intervals of sHA corresponding to the radiographic severity of knee OA for elucidating whether sHA can be useful as a burden of disease marker for individual patient with knee OA. METHODS: 372 women with Kellgren & Lawrence grade (K/L) 1 through 4 painful knee OA were enrolled in this study. The patients included 54 with K/L 1, 96 with K/L 2, 97 with K/L 3, and 118 with K/L 4. Serum samples were obtained from all subjects on the day that radiographs taken. A HA binding protein based latex agglutination assay that employed an ELISA format was used to measure sHA. Age and BMI adjusted one way ANOVA was used to set the reference intervals of sHA. RESULTS: The reference intervals for sHA corresponding to the patients with K/L 4 (49.6 - 66.5 ng/ml) was established without any overlap against to those with K/L 1, 2 and 3, while those with K/L 1, 2 and 3 showed considerable overlap. CONCLUSIONS: These results indicate that sHA can be available as a burden of disease marker for the individuals with severe knee OA (K/L 4), while it is not for those with primary to moderate knee OA (K/L 1-3).

ACL Reconstruction Preserving the ACL Remnant Achieves Good Clinical Outcomes and Can Reduce Subsequent Graft Rupture.

BACKGROUND: Although anterior cruciate ligament (ACL) reconstruction techniques that preserve remnant tissues have been described, complete preservation may be difficult, with little known about its clinical advantages. PURPOSE: To compare clinical outcomes in patients undergoing ACL reconstruction with and without ACL remnant preservation. STUDY DESIGN: Case-control study. METHODS: Of 372 patients who underwent surgical treatment of an ACL injury between September 2006 and July 2010, 154 had no remaining identifiable ligament tissue and were excluded from this study. Attempts were made to preserve the ACL remnant as much as possible in the remaining 218 patients. These patients were divided into 2 groups: those in whom the remnant was preserved (group 1, n = 85) and those in whom the remnant was not preserved (group 2, n = 98). Patients were followed for at least 24 months. Outcomes, including graft rupture, were compared in the 2 groups. RESULTS: Time from injury to surgery was significantly shorter (7.3 ± 16.3 vs 16.0 ± 30.3 months; P < .05) and the preinjury Tegner activity was significantly higher (7.6 ± 1.4 vs 7.1 ± 1.2; P < .05; 95% confidence interval, 1.2-13.7) in group 1 than in group 2. The postoperative negative ratio of the pivot-shift test was similar in the 2 groups (87% vs 81%). Anterior stability of the knee, as measured by a KT-2000 arthrometer, was significantly better in group 1 than in group 2 (1.0 ± 0.8 vs 1.3 ± 1.0 mm; P < .05). ACL graft rupture occurred in 1 patient (1.1%) in group 1 and in 7 patients (7.1%) in group 2 (P < .05). Regression analysis showed that preservation of the remnant decreased the likelihood of graft rupture (odds ratio, 11.2; 95% confidence interval, 1.2-101.7). CONCLUSION: These findings confirmed that preserving the remnant tissue of the ACL may facilitate recovery of function and decrease graft rupture after primary reconstruction.

Stimulation of Osteogenesis in Bone Defects Implanted with Biodegradable Hydroxyapatite Composed of Rod-Shaped Particles under Mechanical Unloading.

The aim of this study was to evaluate the influence of mechanical unloading on the repair of bone defects with implantation of biodegradable bone substitutes. Spherical granules of biodegradable hydroxyapatite composed of rod-shaped particles (RHA) or beta-tricalcium phosphate composed of rod-shaped particles (RTCP) were implanted into a bone defect created in the distal end of the right femur of 8-week-old Wistar rats. Two, 6, 10, and 22 weeks after implantation, part of the sciatic nerve in the thigh was resected and exposed to mechanical unloading for 2 weeks. Then, 4, 8, 12 and 24 weeks after implantation, repair of the bone defect was analyzed. As a control, the bone defect without implantation of ceramic granules was also analyzed. Both RHA and RTCP tended to be reduced, but the reduction was not obvious during the experimental period. At 12 and 24 weeks after implantation, the amount of newly formed bone in the animal implanted with RHA was significantly greater than that at 4 weeks after implantation, but that in the animal implanted with RTCP or without implantation was not significantly different. The number of osteoclasts in the region implanted with RHA was significantly larger than that of the region implanted with RTCP or without implantation at 12 and 24 weeks. The activities of alkaline phosphatase in osteoblasts and tartrate-resistant acid phosphatase in osteoclasts were remarkably increased in the bone defects with implantation compared with those in the bone defects without implantation. These results suggested that RHA stimulated osteogenesis and osteoclastogenesis even after 2 weeks of mechanical unloading, and that RHA could be expected to improve the repair of bone defects in patients under the condition of skeletal unloading.

Femoral tunneled central venous catheters for terminally ill patients with cancer.

BACKGROUND: Oral administration of medication is often difficult in terminally ill patients with cancer. These patients require intravenous routes for high-dose opioid administration and/or parenteral nutrition. When the superior vena cava (SVC) is unsuitable for central vein catheter insertion (i.e., in patients with mediastinal masses involving the SVC), alternative access routes are needed. Of these, the femoral vein is most utilized. In our experience, the femoral tunneled catheter (FTC) is easy and safe to use. We retrospectively studied FTC outcomes in terminally ill patients with cancer. MATERIALS AND METHODS: Charts of consecutive patients admitted to the palliative care unit between April 2008 and December 2011 were reviewed. FTC is inserted into the vein by the single-puncture method using a 16-gauge catheter with a 14-gauge peel-away introducer. RESULTS: Eleven patients underwent FTC insertion. In total, there were 207 days of FTC placement; the mean period in place was 19±15 days. Eight patients received parenteral opioid therapy, high doses in four cases, via FTCs. Complications were incidental arterial puncture and poor infusion rate due to hip joint bending in one case each. Neither catheter-related infection nor clinical venous thrombosis occurred. CONCLUSIONS: FTCs were successfully inserted, with a low complication rate. FTC, a simple technique, might be an acceptable alternative in selected terminally ill patients with cancer, when SVC insertion is difficult or contraindicated.

Anabolic action of parathyroid hormone regulated by the ß2-adrenergic receptor.

Parathyroid hormone (PTH), the major calcium-regulating hormone, and norepinephrine (NE), the principal neurotransmitter of sympathetic nerves, regulate bone remodeling by activating distinct cell-surface G protein-coupled receptors in osteoblasts: the parathyroid hormone type 1 receptor (PTHR) and the ß(2)-adrenergic receptor (ß(2)AR), respectively. These receptors activate a common cAMP/PKA signal transduction pathway mediated through the stimulatory heterotrimeric G protein. Activation of ß(2)AR via the sympathetic nervous system decreases bone formation and increases bone resorption. Conversely, daily injection of PTH (1-34), a regimen known as intermittent (i)PTH treatment, increases bone mass through the stimulation of trabecular and cortical bone formation and decreases fracture incidences in severe cases of osteoporosis. Here, we show that iPTH has no osteoanabolic activity in mice lacking the ß(2)AR. ß(2)AR deficiency suppressed both iPTH-induced increase in bone formation and resorption. We showed that the lack of ß(2)AR blocks expression of iPTH-target genes involved in bone formation and resorption that are regulated by the cAMP/PKA pathway. These data implicate an unexpected functional interaction between PTHR and ß(2)AR, two G protein-coupled receptors from distinct families, which control bone formation and PTH anabolism.

Heterogeneously vancomycin-intermediate Staphylococcus aureus (hVISA) emerged before the clinical introduction of vancomycin in Japan: a retrospective study.

Vancomycin-intermediate Staphylococcus aureus (VISA) and its precursor, heterogeneous VISA (hVISA), are increasingly the cause of vancomycin treatment failure. Prolonged glycopeptide treatment causes the emergence of these pathogens. However, we recently reported that hVISA can be generated by methicillin-resistant S. aureus (MRSA) exposure to imipenem (Katayama et al., Antimicrob Agents Chemother. 53:3190-6). We report here a retrospective prevalence study of VISA and hVISA on 750 MRSA clinical strains isolated from 31 Japanese national university hospitals in 1990, the year before the introduction of injectable vancomycin into clinical use in Japan in 1991. No VISA strain was identified, but population analysis identified 38 hVISA strains (5.1%) from 19 hospitals. We also determined the nucleotide sequences of vraSR, walRK, clpP, and rpoB genes whose mutations are known to be associated with vancomycin resistance. When compared with vancomycin-susceptible MRSA strain N315, six of the 38 hVISA strains possessed nonsynonymous mutations in vraSR, seven in walRK, and two in rpoB genes, Thirteen of 38 (34.2%) hVISA strains possessed at least one of these mutations. Results were consistent with our hypothesis that hVISA was present in Japanese hospitals before the clinical introduction of vancomycin.